Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia

Lian Xu, Zachary R. Hunter, Nicholas Tsakmaklis, Yang Cao, Guang Yang, Jie Chen, Xia Liu, Sandra Kanan, Jorge J. Castillo, Yu Tzu Tai, James L. Zehnder, Jennifer R. Brown, Ruben D. Carrasco, Ranjana Advani, Jean M. Sabile, Kimon Argyropoulos, M. Lia Palomba, Enrica Morra, Alessandra Trojani, Antonino GrecoAlessandra Tedeschi, Marzia Varettoni, Luca Arcaini, Nikhil M. Munshi, Kenneth C. Anderson, Steven P. Treon

Research output: Contribution to journalArticlepeer-review


CXCR4WHIM somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.

Original languageEnglish
Pages (from-to)735-744
Number of pages10
JournalBritish Journal of Haematology
Issue number5
Publication statusPublished - Mar 1 2016


  • WHIM
  • CXCR4
  • IgM MGUS
  • Marginal Zone Lymphoma
  • MYD88 L265P
  • Waldenström macroglobulinaemia

ASJC Scopus subject areas

  • Hematology


Dive into the research topics of 'Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia'. Together they form a unique fingerprint.

Cite this